Abstract

Autoimmune pancreatitis (AIP) often presents with a swollen duodenal papilla,
however, the clinical significance of the duodenal papilla in AIP has not been
fully elucidated. Data have shown swollen duodenal papillae shaped like a pear
and/or with a submucosal tumor having IgG4-bearing plasma cells.
Immunohistopathology has potentially verified duodenal papillitis associated
with AIP. FOXP3-positive lymphocytes are also recognized in AIP. AIP has shown
spontaneous remission and relapse irrelevance to corticosteroid therapy. The
results of a multivariate analysis revealed the absence of a swollen duodenal
papilla as the only significant independent factor predictive of spontaneous
remission in AIP cases. In addition, the results of another multivariate
analysis revealed the presence of a swollen duodenal papilla and the presence of
extrapancreatic lesions as the significant independent factors predictive of
relapse in these cases. Results suggest that the lack of a swollen duodenal
papilla is a predictive factor for spontaneous remission, and thus negates the
need to administer corticosteroids in those AIP patients. In contrast, a swollen
duodenal papilla and the presence of extrapancreatic lesions are risk factors
for relapse, and those AIP patients are candidates for maintenance
corticosteroid therapy to reduce relapse. Therefore, the therapeutic strategy
such as the indication for corticosteroid administration is subject to the
endoscopic features of the duodenal papilla.

Introduction

Useful evidence for the diagnostic criteria and therapeutic strategy for autoimmune
pancreatitis (AIP) has been accumulating [Otsuki et al. 2008; Chari et al.
2006]. A swollen duodenal papilla has often been recognized in AIP [Unno et al.
2002]. However, interpretation of duodenal papillitis associated with AIP has
been challenging. Rarely, the diagnosis has proved difficult when IgG4-seronegative
findings have been observed and/or atypical imaging findings are present such as
focal pancreas swelling mimicking pancreatic cancer (PC) [Woo et al. 2008; Nakazawa et al.
2007; Hardacre et al.
2003]. In such situations, only histopathological evidence has a
diagnostic value for AIP. It is essential to obtain histopathological materials from
the pancreas. However, it is sometimes difficult to retrieve sufficient material to
enable a diagnosis of AIP [Zamboni et al. 2004]. This is partly because taking
pancreatic tissue is difficult and is associated with the risk of complications, and
partly because these specimens does not always present typical AIP pathologic
features due to the small sample size [Bang et al. 2008]. Duodenal
papilla findings reflect pancreaticobiliary diseases [Dimango et al. 1982].
Compared with the pancreatic biopsy material, the specimens taken from the duodenal
papilla can be retrieved in an easy, safe and reliable way [Kubota et al. 2007a]. Data
have suggested that a swollen duodenal papilla with positivity for IgG4
immunostaining was useful in both the diagnosis [Kamisawa et al. 2006] and
prognosis of AIP [Kubota
et al. 2007b]. In this review, we present the
results of our study, the current understanding of duodenal papillitis related to
AIP and the problems to be solved in the future.

Concepts and history of autoimmune pancreatitis

Many AIP patients have undergone pancreas resection following a misdiagnosis of PC
and/or bile duct cancer [Abraham
et al. 2000]. Awareness of AIP is now much more
widespread. However, it is regarded as a systemic disease involved with multiorgan
systems such as sclerosing cholangitis (SC), sclerosing sialadenitis and
retroperitoneal fibrosis [Kamisawa et al. 2003]. Sarles et al.
have described pancreatitis diagnosed on the basis of the immune mechanism [Sarles et al.
1961]. They reported cases with noncalcifying chronic pancreatitis
showing onset with obstructive jaundice, emaciation, hypergammaglobulinemia and
pathological findings with massive infiltration of inflammatory cells in the
pancreas. They also identified the self-immunization phenomenon. Subsequently, with
only a small number of case reports on AIP having been published, the concept of AIP
was defined [Yoshida et
al. 1995]. The Japanese Pancreas Society (JPS) put together
the first diagnostic criteria in the world in 2002 [Members of the criteria committee for autoimmune
pancreatitis of the Japan Pancreas Society, 2002] and revised them in
2006 [Members of the criteria
committee for autoimmune pancreatitis of the Japan Pancreas Society,
2006]. The JPS criteria weight the imaging and serological criteria, whereas
the histology, imaging, serology, other organ involvement and response to therapy
(HISORt) criteria proposed in the US can diagnose AIP only by histopathological
findings [Chari et
al. 2006]. However, the fundamental mechanism has not yet been
proven. Hamano and colleagues described how serum IgG4 is a specific and highly
sensitive marker of AIP [Hamano
et al. 2001]. Following this, two types of AIP were recognized based on
the histopathological findings: lymphoplasmacytic sclerosing pancreatitis (LPSP) and
idiopathic centric pancreatitis (IDCP). The former was first described as LPSP by
Kawaguchi and colleagues in 1991 [Kawaguchi et al. 1991] and
IDCP was first reported by Notohara et al. [Notohara et al.
2003]. Both types of AIP responded well to
corticosteroids, and the JPS regarded the LPSP and IDCP subsets of AIP as another
type of pancreatitis. Characteristic features of AIP include spontaneous remission,
and also relapse even after corticosteroid therapy has been administered [Kubota et al.
2007b; Hirano
et al. 2007; Wakabayashi et al. 2005].
Also, the JPS criteria emphasized the unique type of pancreatitis characterized by
diffuse narrowing of the main pancreatic duct (MPD) on endoscopic retrograde
cholangio-pancreatography (ERCP). As for the therapeutic strategy, Kamisawa and
colleagues described a therapeutic strategy based on the data collected from major
Japanese institutes [Kamisawa
et al. 2009].

The diagnostic criteria and therapeutic strategy are now well established. Atypical
AIP cases were sometimes recognized as having a focal mass together with
IgG4-seronegative findings [Kubota et al. 2007a]. Instead of obtaining pancreatic
biopsy specimens, the usefulness of the endoscopic features and checking the
reactivity of biopsy specimens to IgG4 and/or FOXP3 have been cited [Kubota et al.
2009a]. The features of duodenal papilla associated with AIP have been
described, and we believe that they provide a safe, useful and reliable method to
obtain and investigate biopsy materials in the diagnosis of AIP.

Pathogenesis

The pathogenesis of AIP remains unknown, however, there are several clues. An
association of the HLA haplotype DRB1 *0405-DQB1*0401 with
AIP [Kawa et
al. 2002], antilactoferrin antibodies (anti-LF) mainly located
in the pancreatic acini [Uchida
et al. 2002], anti-carbonic anhydrase II antibodies
(anti-CA-II) chiefly located in the duct cells [Aparisi et al. 2005; Uchida et al.
2002], mediation by the Th1/Th2-type immune response [Okazaki et al.
2000] and upregulation both of the Th2 cytokines and regulatory cytokines
(interleukin-10 [IL-10] and tumor necrosis factor β) [Zen et al.
2007] might play an important role in pathogenesis of AIP. Cytotoxic T
lymphocytes-associated antigen 4 (CTLA-4) was also reported as a susceptibility
factor for AIP [Chang et
al. 2007]. Microbes to break down immune tolerance have been
one of the plausible mechanisms. Recently, a novel antibody, plasminogen-binding
protein (PBP), of Helicobacter pylori was detected in most patients
with AIP. As the PBP peptide is homologous to the human protein ubiquitin-protein
ligase E3 component n-recognin 2, an enzyme highly expressed in the acinar cells of
the pancreas, this suggests that pancreatic acinar cells but not ductal cell may be
the target of the autoimmune activity in patients with AIP [Frulloni et al. 2009].

Conditions of the duodenal papilla associated with autoimmune pancreatitis: a
summary of recent literature

Up to the present, there have been seven articles regarding the association of AIP
with immune-mediated inflammation of the duodenal papilla. Unno and colleagues. were
the first to study the descriptions of the appearance of the main duodenal papilla
in SC [Unno et
al. 2002]. They stated that a swollen duodenal papilla was a
characteristic finding in patients with sclerosing pancreatitis, and T-lymphocyte
infiltration using CD3, CD4, CD8 and L26 antigens was presented in the same paper.
The authors concluded that these features might be useful in the diagnosis of
sclerosing pancreatitis. This is the flagship article regarding the use of duodenal
papilla examination in the diagnosis of AIP. A case report on the association of AIP
with immune-mediated inflammation of the papilla of Vater has been published [Sahin et al.
2004]. The authors additionally reported a study of HLA-DR-antigen expression
regarding the duodenal papilla. Hisa and colleagues presented an interesting case
with lymphoplasmacytic granuloma localized only in the duodenal papilla which was
positively immunostained for IgG4 and originated from the submucosa [Hisa et al.
2008]. This case indicated that duodenal papillitis might be one of the other
organ involvement in patient of AIP. The usefulness of a biopsy of the major
duodenal papilla to diagnose AIP was reported by utilizing IgG4 immunostaining and
the authors concluded that IgG4 immunostaining of biopsy specimens taken from the
major duodenal papilla might support the diagnosis of AIP [Kamisawa et al. 2006]. We
confirmed the findings of the previous study using 17 AIP patients with chronic
alcoholic pancreatitis (CAP) and reported that a swollen duodenal papilla was
recognized in 64.7% of AIP patients [Kubota et al. 2007a]. We
also studied clinicopathological factors predictive of spontaneous remission or
relapse in a small number of cases of AIP
(n=20) and revealed that
negative IgG4 immunostaining of the duodenal papilla appeared to predict a high
frequency of remission without steroid therapy [Kubota et al. 2007b]. This
article is the first to present the significance of the duodenal papilla findings
contributing to the prognosis of AIP. As a diagnostic endoscopic tool for AIP, IgG4
immunostaining of biopsy specimens obtained from the duodenal papilla might be
useful to support a diagnosis of AIP with pancreatic head involvement [Kamisawa et al.
2008]. Differentiating primary SC (PSC) and SC-AIP is challenging. We
clarified the endoscopic findings of the duodenal papilla in patients with SC-AIP
and those with PSC. We found characteristic duodenal papilla features such as a
swollen duodenal papilla that was positive for IgG4 immunostaining; however, PSC
patients tended to have a small duodenal papilla [Kubota et al. 2008]. We
presented the significance of FOXP3+ Treg and IgG4 expression
in the duodenal papilla in patients with AIP [Kubota et al. 2009a]. We
also indicated that the features of the duodenal papilla could not only influence
the diagnosis of AIP but could have a prognostic value. We believe that the
therapeutic strategy can be subject to the features of the duodenal papilla [Kubota et al.
2009b].

Endoscopic features of duodenal papillitis associated with autoimmune
pancreatitis

Duodenal papillitis associated with AIP was recognized not only macroscopically in
swollen duodenal papillae detected by endoscopy, but also microscopically in
duodenal papillae which were not swollen, as mentioned previously [Kamisawa et al.
2006; Sahin
et al. 2004]. An expanding duodenal papilla with
redness can be recognized as ordinary papillitis due to inflammation associated with
gallstones and/or pancreatitis (Figure 1). Regarding the endoscopic features of duodenal papilla in
patients with PC, we also studied using IgG4 immunostaining in eight patients with
PC (not published data) and that there were no special findings on it as Kamisawa
and coworkers reported [Kamisawa
et al. 2008]. Tumorous swollen papillae with or
without erosion on the surface have been recognized in duodenal papillary neoplasms
(Figure 2) [Park et al.
2002; Yamaguchi and
Enjoji, 1987]. Characteristic endoscopic features of AIP, such as a
swollen duodenal papilla, were often overlooked until Unno and colleagues. described
their usefulness [Unno
et al. 2002]. They defined distinctive duodenal
findings associated with AIP when an indistinct border existed between the papilla
and the orad protrusion (Figure
3). We recognized that the swollen duodenal papilla tended to have dilated
capillary veins on their surface. Therefore, we can diagnose AIP based on a swollen
duodenal papilla if the endoscopic features show a swollen duodenal papilla with an
indistinct border between the papilla and the orad protrusion with dilated papillary
veins sometimes present on the surface. Swollen duodenal papillae have been
recognized in some AIP patients but not in others: however, the significance of a
swollen duodenal papilla in the diagnosis and/or prognosis of AIP remains to be
clarified. Duodenal papilla findings in AIP patients should also be regarded as a
supplementary diagnosis of AIP because it was positively reported in
41–59% AIP cases as seen in Table 1 [Kim et al. 2009; Kubota et al.
2007a]. We also reported that the presence of a swollen duodenal papilla
is an independent factor for relapse of AIP [Kubota et al. 2007b]. To
investigate the characteristic findings of duodenal papillae, a part of the duodenal
papilla can be visualized endoscopically by side-view endoscopy which is often used
in ERCP. We usually check and photograph the frontal view and the images are
obtained while looking down at the papilla from the upper part of the duodenum
before cannulation and at least two photographs of each papilla are obtained [Kubota et al.
2007a]. Endoscopic papillary biopsy is an easy and safe method of
obtaining histopathological specimens from the duodenal papilla [Kubota et al.
2007a]. We recommended taking specimens from just below the pancreatic
duct orifice of the duodenal papilla. Up to now, we have photographed 44 AIP cases
and performed an endoscopic papillary biopsy in 32 AIP cases. We have never
experienced postsampling pancreatitis and/or bleeding of AIP patients who have
undergone sampling from the duodenal papilla. Table 2 summarizes the differences in the
endoscopic findings of duodenal papillae among AIP, ordinary papillitis (cases with
PC included) and neoplasm. The important points for the differentiation of AIP,
ordinary papillitis and a neoplasm are the shape, the surface of the duodenal
papilla, the presence of erosion and/or ulcers on the surface, the presence of an
indistinct border, the color of the duodenal papilla, the presence of dilated
capillary veins and the presence of spontaneous bleeding. In short, the swollen
duodenal papilla associated with AIP tend to appear like a submucosal tumor, have a
pear-like shape without any erosion/ulcer on the surface, with an indistinct border,
a normal color, with dilated capillary veins and without spontaneous bleeding.

The reasons why duodenal papillae become swollen in duodenal papillitis associated
with AIP remain unknown. We speculate that duodenal papillitis represents the
inflammation of the pancreaticobiliary condition of AIP. We studied duodenal
papillitis from the points of the subsets of lymphocytes such as AIP, compared with
ordinary papillitis due to alcoholic pancreatitis and/or gallstones [Kubota et al.
2007a]. We identified histopathologically that mild to moderate
lymphocytic infiltration was present in the stroma of the duodenal papilla in AIP
cases (Figure 4). No dense
fibrosis was detected in the duodenal papilla. There were numerous stromal
inflammatory cells infiltrating (SICI) the region just beneath the duodenal papilla
in both patients with AIP and those with CAP. Marked infiltration was particularly
observed in swollen duodenal papillae in patients with AIP. We assessed the SICI
count in AIP patients and found that the average number of cells in SICI per
high-power field (HPF) in AIP patients was significantly higher than that in the
patients with CAP (p<0.05).
Unno and colleagues reported that the cellular infiltrate in the duodenal papilla
consisted predominantly of CD3-positive T lymphocytes and IgG4-positive plasma cells
[Unno et
al. 2002]. It was found that T-cell infiltration tended to be
pronounced in the duodenal papillae of AIP patients compared with CAP patients. We
used CD3 as the T-cell marker (Figure 5) and 79a as the B-cell marker (Figure 6) to compare cell subtypes in AIP
patients. With regards to the cases with a swollen duodenal papilla, more pronounced
T-cell infiltration tended to be recognized in patients with a swollen duodenal
papilla than in those without. Furthermore, more pronounced T-cell infiltration of
the duodenal papilla was also recognized in the patients with immunopositivity for
IgG4 than in those without. Eosinophils tended to be recognized in AIP patients. In
summary, T-cell dominant lymphoplasmacytic infiltration of the duodenal papilla
tended to be recognized in AIP patients. Table 3 summarizes the histopathological
differences in biopsy specimens obtained from duodenal papillae in AIP, ordinary
papillitis and a neoplasm.

Histopathologic differences features of duodenal papilla between
autoimmune pancreatitis, ordinary papillitis and neoplasm.

Immunohistochemical findings in biopsy specimens of duodenal papillitis
associated with autoimmune pancreatitis and its diagnostic value

Sahin and colleagues and Kamisawa and colleagues have reported the usefulness of an
endoscopic biopsy of the duodenal papilla with immunostaining in AIP patients [Kamisawa et al.
2006; Sahin
et al. 2004]. Sahin and coworkers demonstrated that
immune-mediated inflammation of the main duodenal papilla might be associated with
AIP because HLA-DR-antigen expression was recognized in duodenal papillary
epithelial cells [Sahin
et al. 2004]. Positivity for serum IgG4 is
significantly high in AIP [Hamano
et al. 2001]; however, IL-10 induced IgG4 did not
include any proliferative aspect induced by TGF-β. In addition to IgG4,
the forkhead/winged helix family of transcription factor P3 regulatory T cells
(FOXP3+ Treg), a master gene of regulatory T cells
(Treg), is expressed in patients with AIP [Zen et al. 2007]. However,
its local expression and value in biopsy specimens remains unknown. Even if the
macroscopic findings of a swollen duodenal papilla were not present, we could
demonstrate it microscopically with biopsy specimens taken from the duodenal
papilla. We reported that IgG4 and FOXP3 immunostaining was beneficial to the
diagnosis of AIP [Kubota
et al. 2009a]. The results of immunostaining are
shown in Table 4.
Kamisawa and colleagues revealed that the results of endoscopic biopsy using IgG4
immunostaining was useful in the differential diagnosis between patients with AIP
and PC [Kamisawa et
al. 2008]. We hypothesized that FOXP3 showed more comprehensive
positivity in the diagnosis of AIP than that of IgG4. Therefore, we analyzed the
endoscopic features and immunohistopathological findings using FOXP3 and IgG4 in
biopsy specimens obtained from duodenal papillae in patients with AIP to determine
their clinical significance as useful adjuncts for the differential diagnosis in
potential AIP patients with a swollen duodenal papilla [Kubota et al. 2009a]. As
for FOXP3+ Treg expression in the duodenal papilla (Figure 7), significantly
higher levels were detected in AIP than in ordinary papillitis, similarly to IgG4
expression (Figure 8)
(p<0.05 for both). Those
patients in whom the FOXP3+ Treg and IgG4 expression rates
normalized showed a favorable clinical course more than 2 years after corticosteroid
therapy. These expression levels might also have therapeutic value for patients with
AIP. In summary, the result of FOXP3+ and IgG4 upregulation
in the main duodenal papilla improves the sensitivity and specificity in the
diagnosis of AIP.

The diagnosis of SC, which can be caused by AIP and/or PSC, can be difficult. AIP is
often complicated with SC (SC-AIP), which Nakazawa and coworkers classified using
cholangiography to correctly diagnose AIP [Nakazawa et al. 2006].
According to their classification, type 1 occurs only in the lower parts of the
common bile duct and can mimic PC. Type 2 can be misdiagnosed as PSC, and types 3
and 4 are easily mistaken for cholangiocarcinoma. Awareness of this classification
could diminish the misdiagnosis of AIP; nevertheless, some cases remain difficult to
diagnose [Nakazawa et
al. 2007], and unnecessary surgery sometimes occurs. The
endoscopic differentiation of these two conditions has not yet been fully clarified.
We clarified the endoscopic findings of the duodenal papilla in patients with SC-AIP
and those with PSC and determined criteria for the differentiation of these
conditions. We reviewed these records to determine whether the duodenal papillary
findings (swollen papilla/normal papilla/small papilla) might be potentially useful
for differentiating SC-AIP from PSC. Immunohistopathological findings for the
duodenal papilla were also examined using IgG4 among the infiltrating lymphocytes.
The main outcome measurements were as follows: the presence of a swollen duodenal
papilla with IgG4-positive plasma cells was useful for discriminating between SC-AIP
and PSC. A swollen duodenal papilla was observed in 70.4% of the SC-AIP
patients, whereas no swelling of the duodenal papilla was seen in the PSC patients.
A small papilla was recognized in 41.7% of the PSC patients.
IgG4-positive plasma cells in the duodenal papilla were significantly detected in
the SC-AIP patients but not in the PSC patients. Characteristic duodenal endoscopic
papillary features in SC-AIP patients, such as a swollen duodenal papilla and
positive immunostaining for IgG4, might be helpful for discriminating between this
condition and PSC.

The correct timing for terminating corticosteroid therapy remains unknown because
inappropriate or a lack of corticosteroid therapy can cause relapse in AIP [Hirano et al.
2007]. The effect of corticosteroid therapy on the immunopositivity using
FOXP3 and IgG4 of the duodenal papilla were reviewed. A tendency towards a marked
decrease in the stainability of FOXP3-positive lymphocytes and IgG4-positive plasma
cells in the duodenal papilla after corticosteroid administration as compared with
that before the therapy was observed in each case [Kubota et al. 2009a]. AIP
cases showed a relapse rate of around 20–45% [Kamisawa et al.
2009; Hirano
et al. 2007; Kubota et al. 2007b]. The
need to maintain steroid therapy to reduce relapse for AIP was indicated. Predictive
factors including duodenal papillary features have been cited [Kubota et al. 2007b].
Regarding the potential therapeutic value for AIP, the comparison before and after
steroid therapy has not been reviewed. We showed that the FOXP3-positive lymphocyte
count diminished with corticosteroid therapy. We believe that FOXP3 in the duodenal
papilla also has therapeutic value for AIP.

Treatment and prognostic factors

Standard therapeutic strategy and prognosis

AIP is considered to have a favorable prognosis, as AIP patients usually respond
well to corticosteroid therapy [Erkelens et al. 1999].
First-line standard therapy for patients with AIP is corticosteroids. Based on
the analysis of 563 AIP patients nationwide, first induction in AIP patients can
be achieved with prednisolone (PSL) at a dose of 30mg/day for
2–4 weeks. After that, the dose of PSL is tapered gradually
depending on the improvement of serum data and/or imaging findings. Once
remission took place, maintenance therapy with PSL at a dose of
5–7.5mg/day follows for up to 3 years to reduce relapse
[Kamisawa et
al. 2009]. However, some patients with AIP show spontaneous
remission [Kubota et
al. 2007b; Wakabayashi et al.
2005], while others relapse even after corticosteroid therapy [Takayama et
al. 2004]. As for relapse, the relapse rate of AIP was
reported to be 30–50 % based on the long-term follow-up
studies [Kamisawa et
al. 2009; Kubota et al. 2007b],
in particular within the first 3 years after the initial presentation of AIP. A
high serum IgG level, a high serum IgG4 level, the presence of jaundice, diffuse
pancreatic swelling, duodenal papilla swelling and the presence of
extrapancreatic lesions have been reported to increase the risk of relapse.
Hirano and colleagues showed that adequate maintenance therapy is required to
reduce the relapse rate [Hirano et al. 2007]. According to the JPS-published
standard steroid therapy for AIP, they stressed that the remission rate of
steroid-treated AIP was 98%, which was significantly higher than
that of patients without steroid therapy including cases of spontaneous
remission (74%). Moreover, the relapse rate of AIP patients was
significantly lower in those who received steroid therapy (24%) than
those not given steroid therapy (42%). In other words, the relapse
rate of AIP could be reduced by steroid therapy and AIP cases showing
spontaneous remission without relapse may exist [Kamisawa et al.
2009].

The standard steroid therapy for AIP has been proposed, however, the factors
related to spontaneous remission and relapse have not been fully evaluated from
the viewpoint of the features of endoscopic duodenal papilla. We retrospectively
analyzed the clinicopathological features of AIP patients who exhibited
spontaneous remission and/or relapse in an attempt to identify the
relapse-related risk factors in AIP [Kubota et al. 2009b].
Regarding spontaneous remission, patients who entered remission without
corticosteroid therapy had a better outcome without relapse in the study. The
results of a univariate analysis revealed significant association of spontaneous
remission with serum negativity for IgG (<1800mg/dl),
absence of obstructive jaundice, absence of underlying diabetes mellitus,
absence of swelling of the duodenal papilla and localized as opposed to diffuse
pancreatic swelling
(p<0.05). The results of
the multivariate analysis revealed the absence of swollen duodenal papilla as
the only significant independent factor predictive of spontaneous remission in
these cases. On the other hand, according to the results of the univariate
analysis, relapse was associated with diffuse pancreatic swelling, the presence
of duodenal papilla, the presence of extrapancreatic lesions and a history of
corticosteroid therapy
(p<0.05), while a
multivariate analysis revealed the presence of swollen duodenal papillae and the
presence of extra pancreatic lesions as the significant independent factors
predictive of relapse in these cases. Our results suggest that the lack of a
swollen duodenal papilla in AIP patients is a predictive factor for spontaneous
remission, and the administration of corticosteroid in those patients with AIP
is not necessary. In contrast, a swollen duodenal papilla and the presence of
extrapancreatic lesions are risk factors for relapse, and those AIP patients are
candidates for maintenance corticosteroid therapy to reduce relapse. Therefore,
the therapeutic strategy such as the administration of a corticosteroid is
subject to the features of endoscopic duodenal papilla. First, the indications
for corticosteroid therapy should be examined. If the patient does not have
jaundice, exhibits only focal pancreatic swelling and has a normal duodenal
papilla, corticosteroid therapy may not be necessary. As relapse typically
occurs within 2 years following initial treatment and/or diagnosis, patients
with an increased risk of relapse, such as those with a high serum IgG level,
diffuse pancreas swelling, a swollen duodenal papilla and extrapancreatic
lesions, should receive maintenance therapy for more than 6 months and for as
long as 3 years. On the other hand, the long-term natural history of AIP
patients with spontaneous remission remains unknown, however, spontaneous
remission is likely to be recognized in AIP patients without duodenal papilla
swelling and/or diffuse pancreas swelling. We therefore do not always administer
steroids in such patients; however, those patients are at risk for potential
relapse in the future.

Role of endoscopic duodenal papilla features: summary and future outlook

Recognition of endoscopic duodenal papilla findings may be useful in AIP diagnosis.
However, clinically AIP is recognized as being one of two types, one pathologically
demonstrating LPSP, the other IDCP [Park et al. 2009]. A
swollen duodenal papilla might not be seen in the case of the IDCP type. A future
study is warranted to assess whether our results using the endoscopic features of
duodenal papilla as for AIP could be useful for type II AIP. The assessment of
duodenal papillary features observed endoscopically and using biopsy specimens is a
simple, safe, easy and reliable method to make a supplemental diagnosis of AIP. A
swollen duodenal papilla is not always recognized in AIP, however, if it can be
recognized, it is the safest way to obtain histopathological materials. In addition
to the endoscopic features, immunostaining using FOXP3 and/or IgG4 of duodenal
papilla specimens enhanced the supplemental diagnosis of patients with suspected AIP
based on the clinical findings, and enabled deciding on the therapeutic regimen.
Cytokine identification using specimens from the duodenal papilla is promising,
therefore these data have provided with information on which to base the diagnosis
of AIP and an indication whether corticosteroid therapy would be appropriate. A
further prospective, large-number and multi-center study is needed to verify the
usefulness of the duodenal papilla in the diagnosis of AIP.